Cytokine networks and antigen-specific responses have been implicated in the initiation and perpetuation of rheumatoid arthritis (RA). An increasing body of evidence also suggests that some cells in the rheumatoid synovium, including fibroblast-like snoviocytes, exhibit features of transformed cells. These data support the notion that certain aspect of the rheumatoid process become autonomous, although the mechanisms responsible for partial transformation have not been fully elucidated. To explain the tumor-like properties of RA, we proposed a novel hypothesis implicating abnormalities in key regulatory genes, especially the p53 tumor suppressor. In this model, inflammation leads to the accumulation of cytokines, reactive oxygen species (ROS), and nitric oxide (NO) in the joint, which in turn induce DNA damage, p53 activation, and apoptosis in snoviocytes. We proposed that either by spontaneous mutation or due to mutagenesis triggered by ROS or NO, somatic defects in p53 arise and that some cells either fall to undergo apoptosis, gain a growth advanced, or express genes that contribute to tissue destruction. We plan to test this hypothesis as follows; 1) We will determine how the absence of p53 alters the course and destructiveness of inflammatory arthritis using p53 knockout/DBA1 mice and how this can be mitigated using gene therapy; 2) we will determine the mechanisms of mutagenesis in RA joints, including the role of oxidative stress and the expression of DNA mismatch repair enzymes; and 3) we will determine the lineage of cells in the RA synovium that harbor p53 mutations, their location within the joint and when in the course of disease mutations occur.